RESUMO
Memories are stored into long-term representations through a process that depends on protein synthesis. However, a consolidated memory is not static and inflexible and can be reactivated under certain circumstances, the retrieval is able to reactivate memories and destabilize them engaging a process of restabilization known as reconsolidation. Although the molecular mechanisms that mediate fear memory reconsolidation are not entirely known, so here we investigated the molecular mechanisms in the hippocampus involved in contextual fear conditioning memory (CFC) reconsolidation in male Wistar rats. We demonstrated that the blockade of Src family kinases (SFKs), GluN2B-containing NMDA receptors and TrkB receptors (TrkBR) in the CA1 region of the hippocampus immediately after the reactivation session impaired contextual fear memory reconsolidation. These impairments were blocked by the neurotrophin BDNF and the NMDAR agonist, D-Serine. Considering that the study of the link between synaptic proteins is crucial for understanding memory processes, targeting the reconsolidation process may provide new ways of disrupting maladaptive memories, such as those seen in post-traumatic stress disorder. Here we provide new insights into the cellular mechanisms involved in contextual fear memory reconsolidation, demonstrating that SFKs, GluN2B-containing NMDAR, and TrkBR are necessary for the reconsolidation process. Our findings suggest a link between BDNF and SFKs and GluN2B-containing NMDAR as well as a link between NMDAR and SFKs and TrkBR in fear memory reconsolidation. These preliminary pharmacological findings provide new evidence of the mechanisms involved in the reconsolidation of fear memory and have the potential to contribute to the development of treatments for psychiatric disorders involving maladaptive memories.
Assuntos
Receptores de N-Metil-D-Aspartato , Quinases da Família src , Animais , Masculino , Ratos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Medo/fisiologia , Hipocampo/metabolismo , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Quinases da Família src/metabolismoRESUMO
The benefits of aerobic exercises for memory are known, but studies of strength training on memory consolidation are still scarce. Exercise stimulates the release of metabolites and myokines that reaching the brain stimulate the activation of NMDA-receptors and associated pathways related to cognition and synaptic plasticity. The aim of the present study was to investigate whether the acute strength exercise could promote the consolidation of a weak memory. We also investigated whether the effects of strength exercise on memory consolidation and on the BDNF and synapsin I levels depends on the activation of NMDA-receptors. Male Wistar rats were submitted to strength exercise session after a weak training in contextual fear conditioning paradigm to investigate the induction of memory consolidation. To investigate the participation of NMDA-receptors animals were submitted to contextual fear training and strength exercise and infused with MK801 or saline immediately after exercise. To investigate the participation of NMDA-receptors in BDNF and synapsin I levels the animals were submitted to acute strength exercise and infused with MK801 or saline immediately after exercise (in absence of behavior experiment). Results showed that exercise induced the consolidation of a weak memory and this effect was dependent on the activation of NMDA-receptors. The hippocampal overexpression of BDNF and Synapsin I through exercise where NMDA-receptors dependent. Our findings showed that strength exercise strengthened fear memory consolidation and modulates the overexpression of BDNF and synapsin I through the activation of NMDA-receptors dependent signaling pathways.
Assuntos
Consolidação da Memória , N-Metilaspartato , Ratos , Animais , Masculino , N-Metilaspartato/metabolismo , Consolidação da Memória/fisiologia , Ratos Wistar , Maleato de Dizocilpina/farmacologia , Sinapsinas/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Medo/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Environmental enrichment (EE) has been demonstrated to have a beneficial effect on different functions of the central nervous system in several mammal species, being used to improve behavior and cell damage in various neurological and psychiatric diseases. However, little has been investigated on the effect of EE in healthy animals, particularly regarding its impact on memory persistence and the brain structures involved. Therefore, here we verified in male Wistar rats that contextual fear conditioning (CFC) memory persistence, tested 28 days after the CFC training session, was facilitated by 5 weeks of exposure to EE, with no effect in groups tested 7 or 14 days after CFC training. However, a two-week exposure to EE did not affect memory persistence. Moreover, we investigated the role of specific brain regions in mediating the effect of EE on memory persistence. We conducted inactivation experiments using the GABAergic agonist Muscimol to target the basolateral amygdala (BLA), medial prefrontal cortex (mPFC), and CA1 region of the hippocampus (CA1). Inactivation of the BLA immediately and 12 h after CFC training impaired the effect of EE on memory persistence. Similarly, inactivation of the CA1 region and mPFC 12 h after training, but not immediately, also impaired the effect of EE on memory persistence. These results have important scientific implications as they shed new light on the effect of an enriched environment on memory persistence and the brain structures involved, thereby helping elucidate how an environment rich in experiences can modify the persistence of learned information.
Assuntos
Tonsila do Cerebelo , Memória , Ratos , Animais , Masculino , Ratos Wistar , Aprendizagem/fisiologia , Encéfalo , Hipocampo/fisiologia , Córtex Pré-Frontal/fisiologia , MamíferosRESUMO
Memories already consolidated when reactivated return to a labile state and can be modified, this process is known as reconsolidation. It is known the Wnt signaling pathways can modulate hippocampal synaptic plasticity as well as learning and memory. Yet, Wnt signaling pathways interact with NMDA (N-methyl-D-aspartate) receptors. However, whether canonical Wnt/ß-catenin and non-canonical Wnt/Ca2 + signaling pathways are required in the CA1 region of hippocampus for contextual fear memory reconsolidation remains unclear. So, here we verified that the inhibition of canonical Wnt/ß-catenin pathway with DKK1 (Dickkopf-1) into CA1 impaired the reconsolidation of contextual fear conditioning (CFC) memory when administered immediately and 2 h after reactivation session but not 6 h later, while the inhibition of non-canonical Wnt/Ca2+ signaling pathway with SFRP1 (Secreted frizzled-related protein-1) into CA1 immediately after reactivation session had no effect. Moreover, the impairment induced by DKK1 was blocked by the administration of the agonist of the NMDA receptors glycine site, D-Serine, immediately and 2 h after reactivation session. We found that hippocampal canonical Wnt/ß-catenin is necessary to the reconsolidation of CFC memory at least two hours after reactivation, while non-canonical Wnt/Ca2+ signaling pathway is not involved in this process and, that there is a link between Wnt/ß-catenin signaling pathway and NMDA receptors. In view of this, this study provides new evidence regarding the neural mechanisms underlying contextual fear memory reconsolidation and contributes to provide a new possible target for the treatment of fear related disorders.
Assuntos
Memória , Via de Sinalização Wnt , Memória/fisiologia , beta Catenina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Hipocampo/metabolismo , Medo/fisiologiaRESUMO
Objetivo: investigar prevalência e complicações do uso de medicamentos por via intravenosa e por hipodermóclise em pessoas idosas hospitalizadas. Método: estudo transversal, realizado em hospital de Porto Alegre com amostra de 202 pacientes ≥ 60 anos; terapia intravenosa em período superior a 48 horas de punção e/ou hipodermóclise, com prescrição medicamentosa compatível pelas duas vias. Na coleta utilizou-se um instrumento com variáveis sociodemográficas, clínicas e relacionadas à terapia. A análise foi estatística descritiva e inferencial. Resultados: predomínio do uso de medicamentos por via intravenosa (95,5%), mediana de três medicamentos. As complicações foram apenas da terapia intravenosa, sendo a flebite grau II mais prevalente (54,3%) e infiltração grau I em 1% dos casos. Conclusão: a hipodermóclise, apesar de ser uma via segura, ainda é pouco utilizada na prática clínica. Houve alta prevalência do uso da via intravenosa, apesar de que os medicamentos utilizados também poderiam ser administrados por hipodermóclise.
Objective: This study investigated the prevalence and complications of intravenous and hypodermoclysis therapy in hospitalized older adults. Methods: A cross-sectional study conducted at a hospital in Porto Alegre, Brazil, it included 202 patients ≥ 60 years old who received intravenous therapy > 48 hours and/or hypodermoclysis. An instrument was used to collect sociodemographic, clinical and therapy-related data. Descriptive analysis and inferential statistics were used. Results: Intravenous therapy predominated (95.5%), with a median of 3 medications. Complications only occurred in intravenous therapy, with grade II phlebitis being the most prevalent (54.3%) and grade I infiltration occurring in 1% of the cases. Conclusions: Despite its safety, hypodermoclysis is still little used in clinical practice. There was a high prevalence of intravenous use, although the same medications could have also been administered via hypodermoclysis.
Objetivo: investigar prevalencia y complicaciones del uso de medicamentos por vía intravenosa y por hipodermoclisis en ancianos hospitalizados. Método: estudio transversal realizado en hospital de Porto Alegre, Brasil, con una muestra de 202 pacientes ≥ 60 años sometidos a terapia intravenosa por más de 48 horas de punción y/o hipodermoclisis, con prescripción medicamentosa compatible por ambas vías. Para la recolección se utilizó un instrumento con variables sociodemográficas, clínicas y relacionadas a la terapia. El análisis fue estadístico, descriptivo e inferencial. Resultados: predominio del uso de medicamentos por vía intravenosa (95,5%), mediana de tres medicamentos. Hubo complicaciones solamente en la terapia intravenosa, siendo flebitis grado II la más prevalente (54,3%), e infiltración grado I en 1% de los casos. Conclusión: la hipodermoclisis, aunque sea segura, es todavía poco utilizada en la práctica clínica. Hubo alta prevalencia de uso de la vía intravenosa, aunque los medicamentos utilizados también podrían administrarse por hipodermoclisis.
Assuntos
Humanos , Idoso , Idoso de 80 Anos ou mais , Idoso , Cateterismo Periférico , Enfermagem , Hipodermóclise , Segurança do PacienteRESUMO
Wnt proteins activate different signaling pathways, such as the canonical Wnt/ß-catenin signaling pathway and non-canonical ß-catenin-independent signaling pathway and have been related to several functions in central nervous system, including learning and memory. However, whether these signaling pathways are required in the medial prefrontal cortex (mPFC) for fear memory acquisition, consolidation and retrieval remains unclear. To address this question, we submitted male rats to a contextual fear conditioning (CFC) paradigm, and administered canonical Wnt/ß-catenin and non-canonical Wnt/Ca2+ signaling pathways inhibitors, DKK1 and SFRP1, respectively, into the prelimbic (PrL) subdivision of the mPFC at different moments and evaluated short-term and long-term memory acquisition, consolidation and retrieval. We found that blocking canonical Wnt/ß-catenin and non-canonical Wnt/Ca2+ signaling pathways 15 min before or immediately after CFC training had no effect on STM and LTM of CFC, while their blockade 15 min before the retention test prevented the retrieval of STM and LTM of CFC. These results highlight the importance of the mPFC in fear memory retrieval demonstrating that both canonical Wnt/ß-catenin and non-canonical Wnt/Ca2+ signaling pathways participate in this process. To understand how brain systems act on fear memories could provide a new target for the treatment of fear related disorders such as post-traumatic stress disorder and other anxiety disorders.
Assuntos
Medo , beta Catenina , Animais , Cálcio/metabolismo , Medo/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Memória/fisiologia , Córtex Pré-Frontal/metabolismo , Ratos , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
Growing evidence indicates that brain carbonic anhydrases (CAs) are key modulators in cognition, particularly in recognition and aversive memories. Here we described a role for these enzymes also in social recognition memory (SRM), defined as the ability to identify and recognize a conspecific, a process that is of paramount importance in gregarious species, such as rodents and humans. Male adult Wistar rats were submitted to a social discrimination task and, immediately after the sample phase, received bilateral infusions of vehicle, the CAs activator D-phenylalanine (D-Phen, 50 nmols/side), the CAs inhibitor acetazolamide (ACTZ; 10 nmols/side) or the combination of D-Phen and ACTZ directly in the CA1 region of the dorsal hippocampus or in the medial prefrontal cortex (mPFC). Animals were tested 30 min (short-term memory) or 24 h later (long-term memory). We found that inhibition of CAs with infusion of ACTZ either in the CA1 or in the mPFC impaired short-term SRM and that this effect was completely abolished by the combined infusion of D-Phen and ACTZ. We also found that activation of CAs with D-Phen facilitated the consolidation of long-term SRM in the mPFC but not in CA1. Finally, we show that activation of CAs in CA1 and in the mPFC enhances the persistence of SRM for up to 7 days. In both cases, the co-infusion of ACTZ fully prevented D-Phen-induced procognitive effects. These results suggest that CAs are key modulators of SRM and unveil a differential involvement of these enzymes in the mPFC and CA1 on memory consolidation.
Assuntos
Anidrases Carbônicas , Hipocampo , Córtex Pré-Frontal , Reconhecimento Psicológico , Animais , Anidrases Carbônicas/fisiologia , Hipocampo/fisiologia , Masculino , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Wistar , Reconhecimento Psicológico/fisiologiaRESUMO
Alzheimer's disease (AD) causes dementia and memory loss in the elderly. Deposits of beta-amyloid peptide and hyperphosphorylated tau protein are present in a brain with AD. A filtrate of Helicobacter pylori's culture was previously found to induce hyperphosphorylation of tau in vivo, suggesting that bacterial exotoxins could permeate the blood-brain barrier and directly induce tau's phosphorylation. H. pylori, which infects ~60% of the world population and causes gastritis and gastric cancer, produces a pro-inflammatory urease (HPU). Here, the neurotoxic potential of HPU was investigated in cultured cells and in rats. SH-SY5Y neuroblastoma cells exposed to HPU (50-300 nM) produced reactive oxygen species (ROS) and had an increased [Ca2+]i. HPU-treated BV-2 microglial cells produced ROS, cytokines IL-1ß and TNF-α, and showed reduced viability. Rats received daily i.p., HPU (5 µg) for 7 days. Hyperphosphorylation of tau at Ser199, Thr205 and Ser396 sites, with no alterations in total tau or GSK-3ß levels, and overexpression of Iba1, a marker of microglial activation, were seen in hippocampal homogenates. HPU was not detected in the brain homogenates. Behavioral tests were performed to assess cognitive impairments. Our findings support previous data suggesting an association between infection by H. pylori and tauopathies such as AD, possibly mediated by its urease.
Assuntos
Doença de Alzheimer , Helicobacter pylori , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Animais , Glicogênio Sintase Quinase 3 beta/metabolismo , Helicobacter pylori/metabolismo , Fosforilação/fisiologia , Ratos , Espécies Reativas de Oxigênio , Urease/metabolismo , Proteínas tau/metabolismoRESUMO
Carbonic anhydrases (CAs; EC 4.2.1.1) are metalloenzymes present in mammals with 16 isoforms that differ in terms of catalytic activity as well as cellular and tissue distribution. CAs catalyze the conversion of CO2 to bicarbonate and protons and are involved in various physiological processes, including learning and memory. Here we report that the integrity of CA activity in the brain is necessary for the consolidation of fear extinction memory. We found that systemic administration of acetazolamide, a CA inhibitor, immediately after the extinction session dose-dependently impaired the consolidation of fear extinction memory of rats trained in contextual fear conditioning. d-phenylalanine, a CA activator, displayed an opposite action, whereas C18, a membrane-impermeable CA inhibitor that is unable to reach the brain tissue, had no effect. Simultaneous administration of acetazolamide fully prevented the procognitive effects of d-phenylalanine. Whereas d-phenylalanine potentiated extinction, acetazolamide impaired extinction also when infused locally into the ventromedial prefrontal cortex, basolateral amygdala, or hippocampal CA1 region. No effects were observed when acetazolamide or d-phenylalanine was infused locally into the substantia nigra pars compacta. Moreover, systemic administration of acetazolamide immediately after the extinction training session modulated c-Fos expression on a retention test in the ventromedial prefrontal cortex of rats trained in contextual fear conditioning. These findings reveal that the engagement of CAs in some brain regions is essential for providing the brain with the resilience necessary to ensure the consolidation of extinction of emotionally salient events.
Assuntos
Anidrases Carbônicas/metabolismo , Medo/fisiologia , Memória/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Região CA1 Hipocampal/fisiologia , Emoções , Aprendizagem , Masculino , Camundongos , Córtex Pré-Frontal/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos WistarRESUMO
Social recognition memory (SRM) enables the distinction between familiar and strange conspecifics, a fundamental ability for sociable species, such as rodents and humans. There is mounting evidence that the medial prefrontal cortex plays a prominent role both in shaping social behavior and in recognition memory. Glutamate is the major excitatory neurotransmitter in the brain, and activity of its ionotropic receptors is known to mediate both synaptic plasticity and consolidation of various types of memories. However, whether these receptors are required in the medial prefrontal cortex (mPFC) for SRM consolidation remains elusive. To address this issue, we submitted rats to a social discrimination paradigm, administered infusions of NMDA- and AMPA/kainate-receptors antagonists into the prelimbic (PrL) subdivision of the mPFC at different post-encoding time points and evaluated long-term memory retention twenty-four hours later. We found that blocking NMDA receptors immediately after the sample phase, but not 3 h later, impaired SRM consolidation, whereas the blockade of AMPA/kainate receptors immediately and 3 h, but not 6 h after the sample phase, prevented long-term memory consolidation. These results highlight the importance of the mPFC in social cognition and may contribute towards the understanding of the dysfunctional social information processing that underlies multiple neuropsychiatric disorders.
Assuntos
Consolidação da Memória/fisiologia , Córtex Pré-Frontal/fisiologia , Receptores Ionotrópicos de Glutamato/fisiologia , Reconhecimento Psicológico/fisiologia , Percepção Social , Animais , Discriminação Psicológica , Masculino , Ratos Wistar , Receptores de AMPA/fisiologia , Receptores de Ácido Caínico/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologiaRESUMO
Fear memory has an essential role on animal's survival once it induces defensive behavior in response to threats. Among other factors, social support is known to down-regulate the expression of fear conditioned response, representing an important modulator of fear memories. Here we studied the effects of social support during acquisition, retrieval and extinction of contextual fear conditioning (CFC) memory in rats, by exposing the animals to the CFC task either in the absence or in the presence of a conspecific during the training, extinction and/or test sessions. The presence of a conspecific during the training session of CFC resulted in impairment to memory retention as verified in the short- and long-term memory test, suggesting that social support exerts a suppressive effect on the acquisition of CFC. On retrieval, social support decreased the expression of the conditioned fear response - as also seen in the extinction session. Nevertheless, the animals were able to learn the extinction memory as verified in the retention test. Therefore, this study demonstrates the effects of social support at crucial moments in CFC: impairing memory acquisition and favoring its extinction, by reducing the expression of the conditioned fear response with no impairment to the extinction learning.
Assuntos
Extinção Psicológica , Medo/fisiologia , Memória de Longo Prazo/fisiologia , Memória de Curto Prazo/fisiologia , Apoio Social , Animais , Comportamento Animal/fisiologia , Masculino , Ratos , Ratos WistarRESUMO
Extinction is the learned inhibition of retrieval. It is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear-related pathologies such as post-traumatic stress disorder. The serotonin (5-HT) system is positioned to modulate the extinction circuitry via ascending 5-HT projections that innervate certain brain structures including the hippocampus and the basolateral amygdala (BLA). The most recently described serotoninergic receptors 5-HT5A, 5-HT6, 5-HT7 affect different memory processes and so are putative therapeutic targets for disorders related to cognition; however, their role in the extinction of contextual fear conditioning (CFC) has not been studied yet. Here we investigate the role of these receptors in the CA1 region of the hippocampus and the BLA in the extinction of CFC. For this, male rats were implanted with cannulae in the CA1 or in the BLA region through which they received immediately or 3 h after extinction training of CFC infusions of SB699551 (10 µg/side), 5-HT5A antagonist; WAY-208466 (0.04 µg/side), 5-HT6 agonist; SB-271046A (10 µg/side), 5-HT6 antagonist; AS-19 (5 µg/side), 5-HT7 agonist; SB-269970 (5 µg/side), 5-HT7 antagonist. After 24 h, animals were submitted to a 3 min extinction test. Results show that the infusion immediately after extinction training of 5-HT5A, 5-HT6 and 5-HT7 antagonists, and 3 h after extinction training of 5-HT5A and 5-HT7 antagonists in the BLA region, but not in CA1, facilitates the extinction of CFC memory.
Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Receptores de Serotonina/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Encéfalo/fisiologia , Condicionamento Clássico/fisiologia , Medo/psicologia , Hipocampo/fisiologia , Masculino , Memória/fisiologia , Ratos , Ratos Wistar , Receptores de Serotonina/metabolismoRESUMO
Extinction of contextual fear conditioning (CFC) in the presence of a familiar nonfearful conspecific (social support), such as that of others tasks, can occur regardless of whether the original memory is retrieved during the extinction training. Extinction with social support is blocked by the protein synthesis inhibitors anisomycin and rapamycin and by the inhibitor of gene expression 5,6-dichloro-1-ß-d-ribofuranosylbenzimidazole infused immediately after extinction training into the ventromedial prefrontal cortex (vmPFC) but unlike regular CFC extinction not in the CA1 region of the dorsal hippocampus. So social support generates a form of learning that differs from extinction acquired without social support in terms of the brain structures involved. This finding may lead to a better understanding of the brain mechanisms involved in the social support of memories and in therapies for disorders related to dysfunctional fear memories. Thus, here we show that the consolidation of extinction memory with social support relies on vmPFC rather than hippocampus gene expression and ribosomal- and mammalian target of rapamycin-dependent protein synthesis. These results provide additional knowledge about the cellular mechanisms and brain structures involved on the effect of social support in changing behavior and fear extinction memory.
Assuntos
Extinção Psicológica/fisiologia , Hipocampo/fisiologia , Aprendizagem/fisiologia , Córtex Pré-Frontal/fisiologia , Biossíntese de Proteínas/fisiologia , Animais , Anisomicina/farmacologia , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/fisiologia , Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Ratos Wistar , Sirolimo/farmacologia , Apoio SocialRESUMO
Methylphenidate (MPH) is a widely prescribed drug for the treatment of attention-deficit hyperactivity disorder. Findings in the literature suggest that the effects of MPH on memory may result from increased extracellular levels of norepinephrine (NE) and dopamine (DA). Here, we report that the systemic administration of MPH before the acquisition phase in a social discrimination task impaired the retrieval of the social recognition memory (SRM), but made it state-dependent: another administration of MPH before the retention test recovered the SRM. We observed that the induction of state dependency by MPH relies on the ventromedial prefrontal cortex (vmPFC), but not on the CA1 region of the hippocampus (CA1). Also, the inhibitors of NE and DA, nisoxetine and GBR12909, respectively, restored the SRM when infused into the vmPFC. Only the GBR12909 was able to restore the SRM in the CA1, whereas nisoxetine could not restore and even caused an impairment on memory retrieval when infused alone before the retention test. The data suggest that the state-dependence of SRM induced by MPH depends on an influence of both catecholamines on the vmPFC, while NE inhibits the retrieval of SRM on the hippocampus.
Assuntos
Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Hipocampo/efeitos dos fármacos , Metilfenidato/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Comportamento Social , Animais , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Objetivo: Realizar uma revisão da literatura sobre o efeito da D-cicloserina (DCS) no tratamento do Transtorno de estresse pós-traumático (TEPT). Métodos: Foram revisados 14 ensaios clínicos, revisões sistemáticas e meta-análises selecionados na base de dados PubMed que correspondessem aos descritores D-cicloserina e Transtorno de estresse pós-traumático. Resultados: Os resultados mostram-se heterogêneos, incluindo resultados com e sem benefícios clínicos para o uso da DCS, provavelmente devido à diferença de métodos utilizados nos estudos realizados. Entretanto, a DCS apresenta efeito benéfico quando administrada em pacientes com quadros mais graves de TEPT e quando associada à terapia de exposição com realidade virtual. Conclusão: A DCS tem se mostrado uma opção terapêutica promissora quando associada à terapia de exposição; entretanto, mais estudos devem ser realizados para comprovar sua efetividade no tratamento do TEPT.
Aim: To review the literature about the effect of D-cycloserine (DCS) on the treatment of Post-traumatic stress disorder (PTSD). Methods: Were reviewed fourteen clinical trials, systematic reviews and meta-analyzes selected in the PubMed database that corresponded to the descriptors D-cycloserine and Post-traumatic stress disorder. Results: The results are heterogeneous, including results with and without clinical benefit for the use of DCS, probably due to the different methods used in the studies. However, DCS has a beneficial effect when administered to patients with severe PTSD and when associated with virtual reality exposure therapy. Conclusion: It has been shown that DCS is a promising therapeutic choice when associated with exposure therapy, however further studies should be performed to prove its effectiveness in the treatment of PTSD.
Assuntos
Humanos , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , CiclosserinaRESUMO
The insular cortex (IC) receives projections from prefrontal, entorhinal and cingulate cortex, olfactory bulb and basal nuclei and has reciprocal connections with the amygdala and entorhinal cortex. These connections suggest a possible involvement in memory processes; this has been borne out by data on several behaviors. Social recognition memory (SRM) is essential to form social groups and to establish hierarchies and social and affective ties. Despite its importance, knowledge about the brain structures and the neurotransmitter mechanisms involved in its processing is still scarce. Here we study the participation of NMDA-glutamatergic, D1/D5-dopaminergic, H2-histaminergic, ß-adrenergic and 5-HT1A-serotoninergic receptors of the IC in the consolidation of SRM. Male Wistar rats received intra-IC infusions of substances acting on these receptors immediately after the sample phase of a social discrimination task and 24h later were exposed to a 5-min retention test. The intra-IC infusion of antagonists of D1/D5, ß-adrenergic or 5-HT1A receptors immediately after the sample phase impaired the consolidation of SRM. These effects were blocked by the concomitant intra-IC infusion of agonists of these receptors. Antagonists and agonists of NMDA and H2 receptors had no effect on SRM. The results suggest that the dopaminergic D1/D5, ß-adrenergic and serotonergic 5-HT1A receptors in the IC, but not glutamatergic NMDA and the histaminergic H2 receptors, participate in the consolidation of SRM in the IC.
Assuntos
Córtex Cerebral/metabolismo , Consolidação da Memória/fisiologia , Receptores de Neurotransmissores/metabolismo , Reconhecimento Psicológico/fisiologia , Percepção Social , Animais , Cateteres de Demora , Córtex Cerebral/efeitos dos fármacos , Discriminação Psicológica/efeitos dos fármacos , Discriminação Psicológica/fisiologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Masculino , Consolidação da Memória/efeitos dos fármacos , Neurotransmissores/farmacologia , Testes Psicológicos , Ratos Wistar , Receptores de Neurotransmissores/agonistas , Receptores de Neurotransmissores/antagonistas & inibidores , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
Extinction is defined as the learned inhibition of retrieval and is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear disorders. The psychostimulant, methylphenidate (MPH) is known to increase extracellular levels of noradrenaline and dopamine by blocking their reuptake and studies have demonstrated that MPH can modulate hippocampal physiology and/or functions including long-term potentiation (LTP), learning and memory. However, the influence of MPH on fear extinction memory has been insufficiently studied. Here we investigate the effect of MPH infused into the CA1 region of the hippocampus on extinction memory in animals normally incapable of showing contextual fear conditioning (CFC) extinction because of weak training, and the possible mechanisms through which it acts during this process. For this, male Wistar rats with infusion cannulae stereotaxically implanted in the CA1 region were submitted to a weak extinction protocol in a CFC apparatus. Animals that received intra-CA1 infusion of MPH (12.5µg/side) 20min before the extinction training (Ext Tr) expressed less freezing behavior than Veh-treated animals during both Ext Tr and extinction retention Test (Ext Test). Additionally, the administration of MPH+Timolol (1µg/side) or MPH+SCH23390 (1.5µg/side) intra-CA1 20min before the Ext Tr blocked the enhancing effect of the MPH on extinction learning. These results suggest that MPH in the CA1 region of the hippocampus is able to induce the consolidation of extinction memory and this process occurs through both ß-adrenergic and D1/D5 dopaminergic receptors.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Comportamento Animal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Antagonistas de Dopamina/farmacologia , Extinção Psicológica/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Metilfenidato/farmacologia , Receptores Adrenérgicos beta/fisiologia , Receptores Dopaminérgicos/fisiologia , Antagonistas Adrenérgicos beta/administração & dosagem , Animais , Benzazepinas/administração & dosagem , Benzazepinas/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Condicionamento Clássico/efeitos dos fármacos , Antagonistas de Dopamina/administração & dosagem , Medo/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de Dopamina D1/antagonistas & inibidores , Timolol/administração & dosagem , Timolol/farmacologiaRESUMO
Fear memory is the best-studied form of memory. It was thoroughly investigated in the past 60 years mostly using two classical conditioning procedures (contextual fear conditioning and fear conditioning to a tone) and one instrumental procedure (one-trial inhibitory avoidance). Fear memory is formed in the hippocampus (contextual conditioning and inhibitory avoidance), in the basolateral amygdala (inhibitory avoidance), and in the lateral amygdala (conditioning to a tone). The circuitry involves, in addition, the pre- and infralimbic ventromedial prefrontal cortex, the central amygdala subnuclei, and the dentate gyrus. Fear learning models, notably inhibitory avoidance, have also been very useful for the analysis of the biochemical mechanisms of memory consolidation as a whole. These studies have capitalized on in vitro observations on long-term potentiation and other kinds of plasticity. The effect of a very large number of drugs on fear learning has been intensively studied, often as a prelude to the investigation of effects on anxiety. The extinction of fear learning involves to an extent a reversal of the flow of information in the mentioned structures and is used in the therapy of posttraumatic stress disorder and fear memories in general.
Assuntos
Medo/fisiologia , Sistema Límbico/fisiologia , Consolidação da Memória/fisiologia , Córtex Pré-Frontal/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Condicionamento Psicológico , Extinção Psicológica , Hipocampo/fisiologia , Hormônios/fisiologia , Humanos , Plasticidade Neuronal , Neurotransmissores/fisiologia , Transtornos de Estresse Pós-Traumáticos/terapia , Sinapses/fisiologiaRESUMO
For decades there has been a consensus that de novo protein synthesis is necessary for long-term memory. A second round of protein synthesis has been described for both extinction and reconsolidation following an unreinforced test session. Recently, it was shown that consolidation and reconsolidation depend not only on protein synthesis but also on protein degradation by the ubiquitin-proteasome system (UPS), a major mechanism responsible for protein turnover. However, the involvement of UPS on consolidation and reconsolidation of object recognition memory remains unknown. Here we investigate in the CA1 region of the dorsal hippocampus the involvement of UPS-mediated protein degradation in consolidation and reconsolidation of object recognition memory. Animals with infusion cannulae stereotaxically implanted in the CA1 region of the dorsal hippocampus, were exposed to an object recognition task. The UPS inhibitor ß-Lactacystin did not affect the consolidation and the reconsolidation of object recognition memory at doses known to affect other forms of memory (inhibitory avoidance, spatial learning in a water maze) while the protein synthesis inhibitor anisomycin impaired the consolidation and the reconsolidation of the object recognition memory. However, ß-Lactacystin was able to reverse the impairment caused by anisomycin on the reconsolidation process in the CA1 region of the hippocampus. Therefore, it is possible to postulate a direct link between protein degradation and protein synthesis during the reconsolidation of the object recognition memory.
Assuntos
Região CA1 Hipocampal/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Reconhecimento Psicológico/fisiologia , Ubiquitina/metabolismo , Acetilcisteína/análogos & derivados , Acetilcisteína/farmacologia , Animais , Anisomicina/farmacologia , Região CA1 Hipocampal/efeitos dos fármacos , Cateteres de Demora , Inibidores de Cisteína Proteinase/farmacologia , Masculino , Testes Neuropsicológicos , Inibidores da Síntese de Proteínas/farmacologia , Proteólise/efeitos dos fármacos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Ubiquitina/antagonistas & inibidoresRESUMO
Exposure to a novel environment enhances the extinction of contextual fear. This has been explained by tagging of the hippocampal synapses used in extinction, followed by capture of proteins from the synapses that process novelty. The effect is blocked by the inhibition of hippocampal protein synthesis following the novelty or the extinction. Here, we show that it can also be blocked by the postextinction or postnovelty intrahippocampal infusion of the NMDA receptor antagonist 2-amino-5-phosphono pentanoic acid; the inhibitor of calcium/calmodulin-dependent protein kinase II (CaMKII), autocamtide-2-related inhibitory peptide; or the blocker of L-voltage-dependent calcium channels (L-VDCCs), nifedipine. Inhibition of proteasomal protein degradation by ß-lactacystin has no effect of its own on extinction or on the influence of novelty thereon but blocks the inhibitory effects of all the other substances except that of rapamycin on extinction, suggesting that their action depends on concomitant synaptic protein turnover. Thus, the tagging-and-capture mechanism through which novelty enhances fear extinction involves more molecular processes than hitherto thought: NMDA receptors, L-VDCCs, CaMKII, and synaptic protein turnover.